Candida auris uses metabolic strategies to escape and kill macrophages while avoiding robust activation of the NLRP3 inflammasome response

Weerasinghe, Harshini; Simm, Claudia; Djajawi, Tirta M; Tedja, Irma; Lo, Tricia L.; Simpson, Daniel S; Shasha, David; Mizrahi, Naama; Olivier, Françios A B; Speir, Mary; Lawlor, Kate E.; Ben‐Ami, Ronen; Traven, Ana

doi:10.1016/j.celrep.2023.112522

Cited by 21 publications

(12 citation statements)

References 76 publications

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“…Macrophages are the first-in-line immune cells to defend against fungal infection. , C. auris is recognized and engulfed by these immune cells and can quickly replicate inside macrophages. , We therefore wanted to test if MMV022478 and its two most potent analogues could inhibit C. auris growth when phagocytosed by mouse bone marrow-derived macrophages (BMDM).…”

Section: Resultsmentioning

confidence: 99%

“…B11220 grows slower in comparison to isolates of other clades, which may be one explanation for the slight increase in susceptibility. 53 In general, isolates of clade II have been shown to be more susceptible to known antifungal drugs and are the only clade not associated with hospital outbreaks. 51,54 The degree of growth inhibition at 12.5 μM varied significantly with no obvious correlation to clades, suggesting that these differences are isolate-rather than clade-specific.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…67,68 C. auris is recognized and engulfed by these immune cells and can quickly replicate inside macrophages. 53,68 We therefore wanted to test if MMV022478 and its two most potent analogues could inhibit C. auris growth when phagocytosed by mouse bone marrow-derived macrophages (BMDM). To ensure the full viability and integrity of BMDMs, the metabolic activity of the macrophages in the presence of the MMV compounds was measured (Figure 6a).…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…auris clades can differ in their antifungal susceptibility, we tested if all isolates available in our lab showed the same MIC values toward MMV022478. − Only B11220 (clade II) showed full growth inhibition at 12.5 μM while isolates of all other clades had an MIC of 25 μM (Figure b). B11220 grows slower in comparison to isolates of other clades, which may be one explanation for the slight increase in susceptibility . In general, isolates of clade II have been shown to be more susceptible to known antifungal drugs and are the only clade not associated with hospital outbreaks. , The degree of growth inhibition at 12.5 μM varied significantly with no obvious correlation to clades, suggesting that these differences are isolate- rather than clade-specific.…”

Section: Resultsmentioning

confidence: 99%

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Leveraging the MMV Pathogen Box to Engineer an Antifungal Compound with Improved Efficacy and Selectivity against Candida auris

Pan,

Weerasinghe,

Sezmis

et al. 2023

ACS Infect. Dis.

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Fungal infections pose a significant and increasing threat to human health, but the current arsenal of antifungal drugs is inadequate. We screened the Medicines for Malaria Venture (MMV) Pathogen Box for new antifungal agents against three of the most critical Candida species (Candida albicans, Candida auris, and Candida glabrata). Of the 14 identified hit compounds, most were active against C. albicans and C. auris. We selected the pyrazolo-pyrimidine MMV022478 for chemical modifications to build structure–activity relationships and study their antifungal properties. Two analogues, 7a and 8g, with distinct fluorine substitutions, greatly improved the efficacy against C. auris and inhibited fungal replication inside immune cells. Additionally, analogue 7a had improved selectivity toward fungal killing compared to mammalian cytotoxicity. Evolution experiments generating MMV022478-resistant isolates revealed a change in morphology from oblong to round cells. Most notably, the resistant isolates blocked the uptake of the fluorescent dye rhodamine 6G and showed reduced susceptibility toward fluconazole, indicative of structural changes in the yeast cell surface. In summary, our study identified a promising antifungal compound with activity against high-priority fungal pathogens. Additionally, we demonstrated how structure–activity relationship studies of known and publicly available compounds can expand the repertoire of molecules with antifungal efficacy and reduced cytotoxicity to drive the development of novel therapeutics.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Leveraging the MMV Pathogen Box to Engineer an Antifungal Compound with Improved Efficacy and Selectivity against Candida auris

Pan,

Weerasinghe,

Sezmis

et al. 2023

ACS Infect. Dis.

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“… 4 The study of the functionality showed that the four identified proteins were involved in the carbohydrate metabolism process, this being relevant as it has been proven that C. auris escapes and kills macrophages by adapting its glycolytic capacity and depleting the glucose from the macrophages. 40 …”

Section: Discussionmentioning

confidence: 99%

Identification of the Most Immunoreactive Antigens of Candida auris to IgGs from Systemic Infections in Mice

Areitio,

Antoran,

Rodriguez-Erenaga

et al. 2024

J. Proteome Res.

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The delay in making a correct diagnosis of Candida auris causes concern in the healthcare system setting, and immunoproteomics studies are important to identify immunoreactive proteins for new diagnostic strategies. In this study, immunocompetent murine systemic infections caused by non-aggregative and aggregative phenotypes of C. auris and by Candida albicans and Candida haemulonii were carried out, and the obtained sera were used to study their immunoreactivity against C. auris proteins. The results showed higher virulence, in terms of infection signs, weight loss, and histopathological damage, of the non-aggregative isolate. Moreover, C. auris was less virulent than C. albicans but more than C. haemulonii. Regarding the immunoproteomics study, 13 spots recognized by sera from mice infected with both C. auris phenotypes and analyzed by mass spectrometry corresponded to enolase, phosphoglycerate kinase, glyceraldehyde-3phosphate dehydrogenase, and phosphoglycerate mutase. These four proteins were also recognized by sera obtained from human patients with disseminated C. auris infection but not by sera obtained from mice infected with C. albicans or Aspergillus fumigatus. Spot identification data are available via ProteomeXchange with the identifier PXD049077. In conclusion, this study showed that the identified proteins could be potential candidates to be studied as new diagnostic or even therapeutic targets for C. auris.

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Genomic Innovation and Virulence Evolution in the Emerging Human Fungal Pathogen Candida auris

Gifford,

Rhodes,

Wilson

et al. 2024

The Mycota

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Candida auris uses metabolic strategies to escape and kill macrophages while avoiding robust activation of the NLRP3 inflammasome response

Cited by 21 publications

References 76 publications

Leveraging the MMV Pathogen Box to Engineer an Antifungal Compound with Improved Efficacy and Selectivity against Candida auris

Leveraging the MMV Pathogen Box to Engineer an Antifungal Compound with Improved Efficacy and Selectivity against Candida auris

Identification of the Most Immunoreactive Antigens of Candida auris to IgGs from Systemic Infections in Mice

Genomic Innovation and Virulence Evolution in the Emerging Human Fungal Pathogen Candida auris

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